Hsp40DNAJ

Hsp40, also known as DnaJ, refers to a large family of molecular chaperones that regulate protein folding by acting as co-chaperones of the Hsp70 system. The DnaJ/Hsp40 family is named for the bacterial DnaJ protein, and homologs are found in all domains of life. These proteins specifically stimulate the ATPase activity of Hsp70 and help deliver client proteins for folding, translocation, or degradation.

Domain architecture: Most DnaJ family members share a conserved N-terminal J-domain, which contains the HPD motif essential for activation of Hsp70. Based on additional domains they are classified as Type I (J-domain, G/F-rich region, zinc-binding cysteine-rich CRR, plus C-terminal substrate-binding domain), Type II (J-domain and G/F region, but lacking CRR), and Type III (only the J-domain with diverse C-terminal or ancillary modules).

Mechanism and interactions: The J-domain binds Hsp70 and triggers ATP hydrolysis, enabling the chaperone to adopt high-affinity substrate-binding states. The C-terminal regions in many DnaJs recognize hydrophobic segments of unfolded polypeptides, conferring substrate specificity, while dimerization can modulate activity in some members.

Function and significance: DnaJ proteins assist in de novo folding, prevent aggregation, help in protein translocation across membranes, and participate in stress responses and protein quality control. They cooperate with Hsp70s and sometimes with other chaperones to manage misfolded proteins. In eukaryotes, the family expands into numerous DNAJ (Hsp40) homologs (DNAJA, DNAJB, DNAJC), with tissue- and organelle-specific roles, including ER- and mitochondrial proteostasis. Mutations or misregulation are linked to cellular dysfunction and disease in some contexts.